In the daily grind of scientific research, it can sometimes be hard for researchers to see the meaning of their work outside of the lab. But UM Chemistry graduate student Katarina Makaravage, a member of ProfessorMelanie Sanford’s group, has been able to see her work directly affect how medicines are made.

Makaravage developed a new method to produce the radiotracers needed for PET imaging, and it’s already being used to advance potential medicines in collaboration with Allen Brooks, a research investigator in Professor Peter Scott’s lab in UM Department of Radiology.

Dr. Allen Brooks and Katarina Makaravage in front of an automated synthesis chamber at the PET center.

Positron Emission Tomography (PET) is an important medical imaging technique that involves giving patients a small dose of a radioactive molecule. When this radiotracer decays, it emits a positron, which quickly collides with an electron to emit two gamma rays in opposite directions. The two gamma rays are detected simultaneously, allowing the radiologist to pinpoint exactly where the radiotracer was located.

Depending on the type of PET molecule used, doctors can determine different types of three-dimensional functional information, including whether a tumor is cancerous. PET is also used to decide whether a drug being developed in the lab will work in the intended part of the body, knowledge that is key to advancing a potential new medicine.

But it can be nearly impossible to make certain PET molecules because there is such a small amount of the radioactive isotope to work with—less than one nanomole.

In 2014, when former Sanford lab member Dr. Naoko Ichiishi approached Prof. Scott with highly efficient fluorination methods, Scott was excited to join forces and suggested Ichiishi work with Brooks.

Makaravage's new radiofluorination method (DOI: 10.1021/acs.orglett.6b02911). Publications from the collaboration have been made open-access by Professor Peter Scott (UM Radiology).

As Brooks explains, “Fluorine-18 has essentially optimal properties compared to other PET isotopes. You’re looking at [an imaging] resolution of around 1 mm, whereas you’re looking at 4-5 mm for the other isotopes. Fluorine is also usually metabolically stable,” meaning the PET molecule won’t degrade in the body. The radioactive fluorine-18, usually written 18F, also has highly efficient positron decay and an ideal two-hour half-life, which makes it easier to use in humans or in animal testing.

Taking advantage of the optimal properties of 18F meant facing notoriously difficult fluorine chemistry though. That’s where current Sanford lab member Katarina Makaravage came in. Working between her fume hood in Chemistry and the PET Center in Radiology, Makaravage developed a newmethod to add the radioactive 18F label onto molecular tracers of interest.

This new method uses copper to catalyze the addition of 18F to an aromatic tin starting material, one commonly used to generate PET tracers. Not only does the copper-mediated synthesis allow a greater variety of tracers to be made, but it is also significantly faster than the older palladium-catalyzed method, making the production of a dose feasible given the two-hour half life.

Makaravage’s methods can be used on a wide range of compounds, and perhaps most importantly, they still work when the synthesis is moved to a robotic system, tucked away behind leaded glass.

“While the patient gets a very small amount of radiation at the end of the day, the technician producing the PET tracers would be exposed to 10-100 times that amount without automation. Automation also allows for easy reproducibility,” explains Makaravage.

The radiofluorination collaboration between Melanie Sanford’s lab in Chemistry and Peter Scott’s lab in Radiology has spawned a number of highly-citedpublications and an NIH grant. The collaboration will continue to yield improved 18F methods to aid drug discovery and diagnostic PET imaging.

Makaravage says one of the most exciting moments in her research was “when I found out multiple pharmaceutical companies were using my method as the go-to and using it for clinical trials. It was even FDA approved!”